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PEDIATRICS Vol. 109 No. 5 May 2002, pp. 904-908

Occurrence of Omphalocele in Relation to Maternal Multivitamin Use: A Population-Based Study

Lorenzo D. Botto, MD, Joseph Mulinare, MD, MSPH and J. David Erickson, DDS, PhD

From the National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia

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   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Objective. We evaluated the association between mothers’ use of multivitamin supplements and their infants’ risk for omphalocele, a congenital anomaly of the abdominal wall. Omphalocele can occur in certain multiple congenital anomaly patterns with neural tube defects, for which a protective effect of multivitamins with folic acid has been demonstrated.

Methods. We used data from a population-based case-control study of infants born from 1968–1980 to mothers residing in metropolitan Atlanta. Case-infants with nonsyndromic omphalocele (n = 72) were actively ascertained from multiple sources. Control-infants (n = 3029), without birth defects, were selected from birth certificates by stratified random sampling.

Results. Compared with no use in the periconceptional period, periconceptional use of multivitamin supplements (regular use from 3 months before pregnancy through the first trimester of pregnancy) was associated with an odds ratio for nonsyndromic omphalocele of 0.4 (95% confidence interval [CI]: 0.2–1.0). For the subset comprising omphalocele alone or with selected midline defects (neural tube defects, hypospadias, and bladder/cloacal exstrophy), the odds ratio was 0.3 (95% CI: 0.1–0.9). These estimates were similar when the reference group also included women who began using multivitamins late in pregnancy (during the second or third month of pregnancy). The small number of participants limited the precision of subgroup analyses and translated into wide confidence intervals that included unity.

Conclusions. Periconceptional multivitamin use was associated with a 60% reduction in the risk for nonsyndromic omphalocele. These findings await replication from additional studies to confirm the findings, generate more precise estimates, and detail possible mechanisms of actions.

Key Words: omphalocele • epidemiology • prevention • vitamins • malformation • pregnancy

Abbreviations: ABDCCS, Atlanta Birth Defects Case-Control Study • MACDP, Metropolitan Atlanta Congenital Defects Program • OR, odds ratio • CI, 95% confidence interval


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Multivitamin supplements and folic acid might exert a protective effect against several birth defects. For example, clinical trials demonstrated their protective effect for neural tube defects.1–4 Similar effects have been suggested for other defects such as orofacial clefts5–7 and some heart defects,8–10 but the evidence is not as consistent or as strong as with neural tube defects. Some of these anomalies, particularly neural tube defects and orofacial clefts, can occur in the same infant in combination with omphalocele,11 suggesting that these defects might share certain pathogenetic pathways or risk profiles.

To our knowledge, an apparent protective effect of multivitamin use has not yet been shown for omphalocele. We present an evaluation of the association between mothers’ use of multivitamin supplements and the occurrence of omphalocele in their infants, using data from a population-based case-control study.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Study Design
We analyzed data from the Atlanta Birth Defects Case-Control Study (ABDCCS), in which information was gathered in 1982 and 1983 from parents of infants with birth defects (case infants) and parents of infants who did not have birth defects (control infants). Case infants were ascertained through the Metropolitan Atlanta Congenital Defects Program (MACDP), a population-based registry in operation since 1968 that ascertains infants with birth defects born to mothers residing in the 5-county metropolitan Atlanta area. Registry staff actively ascertains structural birth defects among stillborn and among live born infants whose defects are diagnosed during the first year of life. Sources of information include vital records, medical records from birthing hospitals, pediatric and specialty wards, and cytogenetic laboratories.

All infants with birth defects ascertained through MACDP and born from January 1, 1968–December 31, 1980 were eligible for entrance in the ABDCCS. The control group was a 1% stratified random sample of infants without birth defects born during the same period that was frequency-matched to the case group by hospital of birth, calendar quarter of birth, and race. Details of the design and procedures of the ABDCCS have been published.12,13

Case Review and Classification
We selected as case-participants all live born and stillborn infants with a diagnosis of omphalocele. One of us, blind to exposure status, reviewed registry records for all infants with a diagnosis of omphalocele or gastroschisis to identify all cases with the former condition and reduce misclassification. Each case of omphalocele thus identified was assigned to 1 of 3 mutually exclusive clinical groups: 1) isolated (nonsyndromic), if omphalocele was the only major anomaly present; 2) multiple (nonsyndromic), if other major congenital anomalies were also present; or 3) syndromic, if a genetic or teratogenic syndrome (eg, Beckwith-Wiedemann syndrome, chromosomal trisomies, congenital rubella) was diagnosed. Syndromic cases were then excluded.

In addition, we classified cases in the multiple category into 5 mutually exclusive subgroups based on the pattern of associated anomalies. The first group included phenotypes within the spectrum of bladder and cloacal exstrophy sequence.14,15 Typically these phenotypes included exposed wall of bladder, incomplete fusion of genital tubercles with epispadias, and separated pubic rami with inguinal herniae (bladder exstrophy); and exstrophied cloaca, imperforate anus, and lumbosacral spina bifida (cloacal exstrophy). We included in this group also cases of ompholocele with imperforate anus and spina bifida, even in the absence of exstrophied bladder or cloaca. The second group comprised cases of omphalocele with neural tube defects alone, except for 1 infant who also had cleft lip and palate. The third group comprised cases of omphalocele with hypospadias alone, with or without inguinal hernias. The fourth group included cases of omphalocele with heart defects, with or without diaphragmatic hernia or anomalies of the thoracic wall (cleft or absent sternum). This group therefore included cases reminiscent of cleft sternum, absent sternum, and pentalogy of Cantrell phenotypes.16– 19 The fifth group comprised other phenotypes including those of the limb-body wall sequence.

Exposure Assessment
Information on a variety of exposures, including vitamin use, had been obtained during 1982–1983 through telephone interviews. The complete questionnaire has been published.12 The classification of multivitamin exposure was based mainly on the mothers’ responses to 3 questions: 1) At any time during the period from 3 months before the pregnancy through the first 3 months of the pregnancy, did you take any vitamins regularly, that is, at least 3 times a week? 2) What type of vitamins did you take? That is, were they multivitamins or were they a single vitamin like vitamin C or vitamin A? 3) In which months during this period did you take the vitamin(s)?

Based on the answers, we grouped mothers into 6 mutually exclusive exposure groups: 1) nonusers, if they had reported no regular use of multivitamins during the 6-month period from 3 months before pregnancy through the third month of pregnancy (some might have started after the third month of pregnancy); 2) late postconceptional users, if they reported regular multivitamin use beginning from the second month of pregnancy; 3) early postconceptional users, if they reported regular multivitamin use beginning in the first month of pregnancy; 4) periconceptional users, if they reported regular multivitamin use from 3 months before pregnancy through the third month of pregnancy; 5) other users, if they reported other or discontinuous patterns of multivitamin use; and 6) unknown/uncodable. Regular multivitamin use was defined as taking a multivitamin at least 3 times a week. Although some information was gathered on the brand of the supplement, such information was limited and did not allow us to evaluate to our satisfaction the role of different brands and types of multivitamin supplements.

Exposure Contrast
The formation of the ventral body wall is a complex and yet poorly understood process.20 Although the development of the ventral wall stretches through embryogenesis, it begins very early as the embryonic disk starts folding into the yolk sac and body stalk during the first month postfertilization.20 For this reason, and in light of the findings relative to the protective effect of multivitamin with respect to neural tube defects, we chose periconceptional multivitamin use (group 4) as our primary exposure category. We compared this group of women to those who did not use supplements throughout the first trimester (group 1). We also conducted additional analyses using a second comparison group, which included group 2 (mothers who started multivitamin use after the first month of pregnancy) in addition to group 1, because we speculated that use after the first month of pregnancy was likely to have had only a small effect on the development of the ventral wall.

Relative Risk Estimation
We examined contingency tables for the main exposure variables and covariates to look for confounding and interaction. We constructed logistic regression models to take into account potential confounders. Potential confounders included period of child’s birth, and maternal education, race, age, smoking, alcohol use, diabetes, and chronic diseases, including diabetes mellitus. We present adjusted risk estimates for case-groups with more than 10 participants, and present unadjusted estimates for the others. We used the Fisher exact test procedures to estimate the confidence intervals for contrasts with no exposed cases.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
The overall participation rate in the ABDCCS was 71% for mothers of control infants and 69% for mothers of infants with birth defects. Case review identified 72 cases of omphalocele (Table 1). Mothers of case- and control-infants showed similar findings, although case-mothers were more likely to be 20 to 24 years old and less likely to drink alcohol (Table 2). Their infants were also more likely to have been born in the earlier period of the study.


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  		TABLE 1. Distribution of Omphalocele, by Diagnosis and Clinical Phenotype, ABDCCS, 1968– 1980

 

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  		TABLE 2. Findings Among Mothers of Infants With Omphalocele (Cases) and Mothers of Infants Without Birth Defects (Controls), ABDCCS, 1968–1980

 
Compared with no use during the first trimester of pregnancy (Table 3), periconceptional multivitamin use was associated with a 60% apparent reduction in risk for nonsyndromic omphalocele (odds ratio [OR]: 0.40; 95% confidence interval [CI]: 0.2–1.0). This apparent risk reduction appears to have been driven by certain phenotypic subgroups such as isolated omphalocele or omphalocele associated with selected midline defects (Table 3). These subgroups, however, included only a small number of participants, limiting statistical power (which for the main contrasts was under 20% to detect a halving of the risk, rising to above 85% to detect relative risk of 0.1, for a 2-tailed {alpha} error of 5%). The limited statistical power translated into wide confidence intervals, which often included unity (ie, the estimate of no effect) even when the point estimates suggested strong protective effects.


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  		TABLE 3. Estimated Relative Risk for Nonsyndromic Omphalocele, by Phenotype, in Relation to Periconceptional Use of Multivitamin Supplements, ABDCCS, 1968–1980

 
We obtained similar risk estimates when we used the second reference group, which also included women who started using multivitamin supplements after the first of month of pregnancy (Table 3, right section). Overall, adjusted and unadjusted ORs were similar, suggesting that there was little individual or aggregate confounding.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
Omphalocele affects approximately 1 in 4000 to 6000 pregnancies, although temporal, ethnic, and geographic variations have been reported.21–26 Although omphalocele can be an isolated defect, it often occurs in association with other anomalies, either as part of chromosomal or single-gene disorders (eg, trisomies 13 and 18, acrocallosal and hydrolethalus syndromes27) or of multiple congenital anomaly patterns of unknown origin such as the OEIS complex (omphalocele, exstrophy of bladder, imperforate anus, spina bifida).28–31 The latter associations are of particular interest as they suggest that, at least in some cases, these structurally distinct anomalies might share causal factors or developmental mechanisms. At present, however, the causes of omphalocele and the mechanisms underlying its development are largely unknown.32 Our main finding, that mothers’ periconceptional multivitamin use reduced by 60% the infants’ risk for omphalocele, suggests a role for more investigation into the role of vitamins and micronutrients in the cause and prevention of omphalocele. The additional finding that such apparent risk reduction might extend beyond isolated cases to include those associated with neural tube defects and other midline defects also suggests the possibility of pleiotropic effects on a larger group of malformations.

However, the interpretation of the findings should take into account the limitations and strengths of the study. Bias (particularly recall and selection bias), confounding, and chance could all account for effects of the magnitude we report. Recall bias is of concern because of the long delay (2–12 years) between infant’s birth and mother’s interview. Recall bias might have been a factor, for example, if the women in the study considered not taking vitamins from before conception as an adverse exposure, and, simultaneously, if women of affected children recalled or reported such lack of use more completely than women of unaffected children. Selection bias may have been a factor if, for example, a disproportionate amount of mothers of affected infants who used supplements chose not to participate to the study. Although these events are certainly possible, we think they are unlikely, as in the early 1980s the inverse relation between vitamins and birth defects was not widely known nor accepted, and because there is no evidence for an inverse relation between vitamin use and study participation. Confounding by factors associated with multivitamin use also remains a possibility. Controlling for several maternal and demographic factors did not change appreciably the risk estimates, suggesting there was little individual or aggregate confounding. Nevertheless, unmeasured confounding (eg, by diet) remains a possible explanation for the findings. We were also unable to evaluate the presence and effects of specific vitamins. Finally, the results may have arisen by chance alone. The small number of affected participants limited the precision of the estimates, which were associated with wide CIs often including unity.

The major strengths of the study stem from certain elements of its design. Case infants were actively ascertained, using multiple sources, from a geographically defined residential population. Control infants were frequency-matched to the case-group infants by a stratified random sampling procedure. Comparability of reports from case and control mothers was enhanced by the use of a structured interview, which covered a wide range of potential exposures, not only vitamin use.

When trying to integrate our findings with those in the literature, one is confronted with a scarcity of data that directly evaluate omphalocele in relation to micronutrient intake. For example, the major observational studies and clinical trials on vitamin use and birth defects either did not include or report findings on omphalocele, or, as with the Hungarian randomized clinical trial,3,8 they were not large enough to evaluate relatively uncommon anomalies such an omphalocele. Micronutrient metabolism in omphalocele is also largely unknown, though low B12 levels in affected pregnancies were noted in one report, a finding that, interestingly, was present also in pregnancies complicated by neural tube defects.33

One is then left with indirect data of 2 types. The first type suggests that omphalocele might share some common etiologic and developmental pathways with a certain other anomalies such as neural tube defects. Evidence in favor of this hypothesis derives from clinical and epidemiologic studies linking omphalocele with spina bifida and patterns of multiple congenital anomalies such as the OEIS complex (omphalocele, exstrophy of the bladder, imperforate anus, spina bifida).28–31 Parallel evidence is increasingly generated by experimental molecular genetics. For example, mice lacking the imprinted Cdk inhibitor p57 (KIP2), implicated in Beckwith-Wiedemann syndrome, develop abdominal wall defects, cleft palate and other defects.34 In another study, mice lacking calreticulin, a protein implicated in calcium signaling and numerous cellular functions, developed omphalocele, neural tube defects, and heart defects.35

The second type of indirect data builds on the first by suggesting that the risk for some of these anomalies associated with omphalocele might be reduced by multivitamin use, thus supporting the plausibility for an effect on omphalocele. Such effect is clearest and best-known for neural tube defects1–4,36 but might extend to other anomalies including some of the OEIS spectrum such as anorectal atresia.37 Notably, in our data set, of the several dozen anomalies evaluated in the past, the few were found to be inversely related to multivitamin use included some of these anomalies such as neural tube defects,38 some heart defects,10,39 and orofacial clefts.40

These types of data, together with our findings, do not establish conclusively a relation between omphalocele and multivitamin supplements, but, in our view, they support its plausibility and are presented to encourage additional studies. Such studies can take different forms. First, direct evidence can come from clinical and epidemiologic (typically case-control) studies of vitamins and omphalocele. Particularly valuable will be those studies that use biomarkers, rather than maternal reports alone, to assess micronutrient exposure; those that can examine the role of single multivitamin components; and those that can evaluate interactions between micronutrient status and genetic polymorphisms related to micronutrient metabolism, in the mother and fetus. A potential analytic challenge for such studies in countries such as the United States where flour fortification with folic acid was recently implemented is the possible dilution of the effect of supplements (if folic acid is involved). On the other hand, fortification also represents a powerful opportunity to examine the effect of folic acid alone in a large birth population, by monitoring the changes in the occurrence of omphalocele before and after the implementation of fortification.

Animal and in vitro studies can also provide valuable evidence, particularly with regard to the molecular and developmental pathways that might be involved. For example, in both the animal studies cited above,34,35 although the affected molecules were dissimilar, the authors reported alterations in apoptosis in the affected animals.34,35 Such evidence, if confirmed, might suggest links among apparently dissimilar outcomes and between outcomes and exposures. For example, it might be relevant to note that several groups have shown that apoptosis can be influenced by folate levels in culture media. Specifically, lack of folate increases apoptosis,41–43 whereas its restoration rescues the folate-deficient apoptotic cells.44, 45 Although they remain entirely speculative, such connections can nevertheless be tested in appropriate animal models.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
We report an apparent risk reduction for omphalocele among mothers who used multivitamin supplements regularly in the periconceptional period. Whether this represents an additional benefit of multivitamin supplements it remains unclear, as our findings await careful replication, clear confirmation, and further delineation. If correct, however, such evidence could help ensure that some infants who would otherwise be born with this potentially severe birth defect are instead born healthy.


   ACKNOWLEDGMENTS
 
We thank the 2 anonymous reviewers for helpful comments.


   FOOTNOTES
 
Received for publication Oct 1, 2001; Accepted Jan 17, 2002.

Reprint requests to (L.D.B.) National Center on Birth Defects and Developmental Disabilities, Mailstop F-45, Centers for Disease Control and Prevention, 4770 Buford Hwy NE, Atlanta, GA 30341. E-mail: lbotto{at}cdc.gov


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics

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